scholarly journals Exposure Measurements on Biomimetic Lobules Using Virtual Experiments to Help Improve IVIVE

10.29007/hjfc ◽  
2020 ◽  
Author(s):  
Preethi Krishnan ◽  
Lopamudra Dutta ◽  
Andrew Smith ◽  
Glen Ropella ◽  
Ryan Kennedy ◽  
...  
Keyword(s):  
Hepatic Clearance ◽  
Intrinsic Clearance ◽  
Central Vein ◽  
Unbound Fraction ◽  
Hepatic Disposition ◽  
Liver Model ◽  
New Chemical Entities ◽  
Model Drug

The in vitro-in vivo extrapolation (IVIVE) methods used currently to predict the hepatic clearance of new chemical entities are plagued by poorly understood inaccuracies. To begin identifying plausible sources, we challenge two of core hypotheses. Hypothesis-1: the intralobular micro-anatomical organization of hepatocytes (HPCs) can be abstracted away. By accepting that hypothesis, one can assume that intrinsic clearance per HPC is essentially the same in vitro and in vivo, and thus an IVIVE method can employ a simplified liver model, typically the “well-stirred” liver model. Hypothesis-2: when the simplified liver model is the “parallel tube model,” drug concentration decreases exponentially from portal to central vein. When either simplified liver model is used, a core assumption is that intrinsic clearance is directly proportional to the unbound fraction of drug. A barrier to progress has been the fact that it is currently infeasible to challenge the two hypotheses using wet-lab experiments. In this work, we challenge virtual counterparts of the two hypotheses by experimenting on virtual mice in which hepatic disposition and clearance are consequences of concretized model mechanisms that have met several demanding requirements, including the following. The virtual liver’s structure and organization are strongly analogous to those of an actual liver, and the hepatic disposition and clearance of several virtual compounds have achieved quantitative validation targets. We study two virtual compounds. Compound-1 simulates the extreme of low-clearance, highly permeable compounds. Compound-2 simulates a highly permeable compound exhibiting maximum intrinsic clearance. We simulate changes in unbound fraction by changing the probability (pEnter) that a Compound-1 or -2 will enter an adjacent HPC during a simulation cycle. Compound-1 and -2 HPC exposure rates do not decrease from portal to central vein: they increase, and that contradicts both hypotheses. Further, the relationship between exposure rates and pEnter is nonlinear. The insights achieved help explain the frequently reported underprediction of in vivo hepatic clearance values. We suggest that IVIVE methods can be improved by utilizing a liver model that couples a biomimetic representation of intralobular HPC organization with biomimetic representations of intrahepatic disposition dynamics.

scholarly journals Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo

10.29007/t4kv ◽  
2020 ◽  
Author(s):  
Lopamudra Dutta ◽  
Preethi Krishnan ◽  
Andrew Smith ◽  
Ryan Kennedy ◽  
Glen Ropella ◽  
...  
Keyword(s):  
Hepatic Clearance ◽  
Intrinsic Clearance ◽  
Quasi Steady State ◽  
Exposure Rate ◽  
Virtual Experiments ◽  
Mitigating Factors ◽  
Virtual Mouse ◽  
In Vivo Extrapolation

An improved understanding of in vivo ⇔ in vitro changes is crucial in identifying and mitigating factors contributing to in vitro–in vivo extrapolation (IVIVE) inaccuracies in predicting the hepatic clearance of substances. We argue that a model mechanism-based virtual culture (vCulture) ⇔ virtual mouse (vMouse) (or vRat or vHuman) experiment approach can identify factors contributing to IVIVE disconnects. Doing so depends on having evidence that six Translational Requirements have been achieved. We cite evidence that the first four have been achieved. The fifth Requirement is that differences in measures of vCompound disposition between vCulture and vMouse are attributable solely to the micro-architectural, physiomimetic features, and uncertainties built into the vLiver and vMouse but are absent from the vCulture. The objective of this work is to first improve on a vCulture architecture used previously and then use results of virtual experiments to verify that its use enables the fifth Translational Requirement to be achieved. We employ two different idealized vCompounds, which map to highly permeable real compounds at the extreme ends of the intrinsic clearance spectrum. Virtual intrinsic clearance = Exposure rate per vHPC. At quasi-steady state, results for vCompound-1 are independent of the dosing rate. The average per-vHPC Exposure rates (taken over the whole vLiver in vMouse experiments) are the same (within the variance of the Experiments) as those in vCulture. However, they are location dependent within the vLiver. For vCompound-2, there are dosing rate differences and average per-vHPC Exposure rates within the vLiver are also location dependent. When we account for dosing rate differences, we see again that average per-vHPC Exposure rates averaged over the whole vLiver in vMouse experiments are the same as those in vCulture. Thus, the differences in per vHPC Exposure rate within the vLiver for both vCompounds are attributable solely to the micro-architectural and physiomimetic features built into the vLiver and vMouse but are absent from the vCulture. The results verify that the fifth Translational Requirement has been achieved.

scholarly journals Assessing Toxicokinetic Uncertainty and Variability in Risk Prioritization

2019 ◽  
Vol 172 (2) ◽  
pp. 235-251 ◽  
Author(s):  
John F Wambaugh ◽  
Barbara A Wetmore ◽  
Caroline L Ring ◽  
Chantel I Nicolas ◽  
Robert G Pearce ◽  
...  
Keyword(s):  
Measurement Uncertainty ◽  
Uncertainty Propagation ◽  
Hepatic Clearance ◽  
Biological Variability ◽  
Vitro Assay ◽  
Unbound Fraction ◽  
Risk Prioritization ◽  
Uncertainty Estimates

Abstract High(er) throughput toxicokinetics (HTTK) encompasses in vitro measures of key determinants of chemical toxicokinetics and reverse dosimetry approaches for in vitro-in vivo extrapolation (IVIVE). With HTTK, the bioactivity identified by any in vitro assay can be converted to human equivalent doses and compared with chemical intake estimates. Biological variability in HTTK has been previously considered, but the relative impact of measurement uncertainty has not. Bayesian methods were developed to provide chemical-specific uncertainty estimates for 2 in vitro toxicokinetic parameters: unbound fraction in plasma (fup) and intrinsic hepatic clearance (Clint). New experimental measurements of fup and Clint are reported for 418 and 467 chemicals, respectively. These data raise the HTTK chemical coverage of the ToxCast Phase I and II libraries to 57%. Although the standard protocol for Clint was followed, a revised protocol for fup measured unbound chemical at 10%, 30%, and 100% of physiologic plasma protein concentrations, allowing estimation of protein binding affinity. This protocol reduced the occurrence of chemicals with fup too low to measure from 44% to 9.1%. Uncertainty in fup was also reduced, with the median coefficient of variation dropping from 0.4 to 0.1. Monte Carlo simulation was used to propagate both measurement uncertainty and biological variability into IVIVE. The uncertainty propagation techniques used here also allow incorporation of other sources of uncertainty such as in silico predictors of HTTK parameters. These methods have the potential to inform risk-based prioritization based on the relationship between in vitro bioactivities and exposures.

In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes

2021 ◽  
Vol 16 ◽  
Author(s):  
Xiangli Zhang ◽  
Qin Shen ◽  
Yi Wang ◽  
Leilei Zhou ◽  
Qi Weng ◽  
...  
Keyword(s):  
Bile Acid ◽  
Phase I ◽  
Rat Liver ◽  
Deoxycholic Acid ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Rat Liver Microsomes ◽  
Camptothecin Analogues

Background: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues by introducing deoxycholic acid in 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. Objective: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). Methods: Phase Ⅰ and Phase Ⅱ metabolism of E2 and G2 in rat liver microsomes were performed respectively, and the mixed incubation of phase I and phase Ⅱ metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. Results: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7mL/min. mg protein, more than three times of that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. Conclusion: These findings suggested that E2 and G2 have similar biotransformation pathways except some difference in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).

Development of Natural Bioactive Alkaloids: Anticancer perspective

2021 ◽  
Vol 21 ◽  
Author(s):  
Ashish Patel ◽  
Ravi Vanecha ◽  
Jay Patel ◽  
Divy Patel ◽  
Umang Shah ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Low Cost ◽  
Chemical Compounds ◽  
Cost Effective ◽  
Drug Discovery And Development ◽  
Anticancer Properties ◽  
Antimetastatic Activity ◽  
New Chemical Entities

: Cancer is a frightful disease that still poses a 'nightmare' worldwide, causing millions of casualties annually due to one of the human race's most significant healthcare challenges that requires a pragmatic treatment strategy. However, plants and plant-derived products revolutionize the field as they are quick, cleaner, eco-friendly, low-cost, effective, and less toxic than conventional treatment methods. Plants are repositories for new chemical entities and have a promising cancer research path, supplying 60% of the anticancer agents currently used. Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery and development. However, some alkaloids derived from natural herbs display anti-proliferation and antimetastatic activity on different forms of cancer, both in vitro and in vivo. Alkaloids have also been widely formulated as anticancer medications, such as camptothecin and vinblastine. Still, more research and clinical trials are required before final recommendations can be made on specific alkaloids. This review focuses on the naturally-derived bioactive alkaloids with prospective anticancer properties based on the information in the literature.

scholarly journals In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits

2017 ◽  
Vol 46 (1) ◽  
pp. 335-347 ◽  
Author(s):  
Yu-xing Fei ◽  
Tian-hong Zhang ◽  
Jing Zhao ◽  
He Ren ◽  
Ya-nan Du ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Protein Binding ◽  
Plasma Concentrations ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Pharmacokinetics And Pharmacodynamics ◽  
In Vivo Evaluation

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.

Identification of human cytochrome P 450 s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data

2003 ◽  
Vol 59 (5-6) ◽  
pp. 429-442 ◽  
Author(s):  
Xue-Qing Li ◽  
Anders Bj�rkman ◽  
Tommy B. Andersson ◽  
Lars L. Gustafsson ◽  
Collen M. Masimirembwa
Keyword(s):  
Hepatic Clearance ◽  
Human Cytochrome ◽  
Cytochrome P 450 ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals Proposal of a Pharmacokinetically Optimized Dosage Regimen of Antibiotics in Patients Receiving Continuous Hemodiafiltration

2011 ◽  
Vol 55 (12) ◽  
pp. 5804-5812 ◽  
Author(s):  
Takehito Yamamoto ◽  
Nobuhiro Yasuno ◽  
Shoichi Katada ◽  
Akihiro Hisaka ◽  
Norio Hanafusa ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Clearance ◽  
Minor Effect ◽  
Optimal Dosage ◽  
Continuous Hemodiafiltration ◽  
Unbound Fraction ◽  
Artificial Plasma

ABSTRACTThe aim of the study was to quantitatively predict the clearance of three antibiotics, amikacin, vancomycin, and teicoplanin, during continuous hemodiafiltration (CHDF) and to propose their optimal dosage in patients receiving CHDF. For this goal,in vitroCHDF experiments with a polyacrylonitrile (PAN) membrane were first performed using these antibiotics, and then the clearances were compared within vivoCHDF situations determined in 16 critically ill patients. Thein vitroCHDF clearances were described as the product of the outflow rate of a drain (Qoutflow) and the drug unbound fraction in artificial plasma, indicating that drug adsorption to the PAN membrane has minor effect on drug clearance in our settings. The observedin vivoclearances also agreed very well with the predicted values, with a product ofQoutflowand plasma unbound fraction, when residual creatinine clearance (CLCR) was taken into account (within a range of 0.67- to 1.5-fold for 15 of 16 patients). Based on these results, a nomogram of the optimized dosages of amikacin, vancomycin, and teicoplanin was proposed, and it was evident thatQoutflowand residual CLCRare major determinants of the dosage and dosing interval for these antibiotics. Although the applicability needs to be confirmed with another type of membrane or higherQoutflow, our nomogram can help determine the dosage setting in critically ill patients receiving CHDF.

Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics: Itraconazole as a Model Drug

2016 ◽  
Vol 33 (7) ◽  
pp. 1782-1794 ◽  
Author(s):  
Ahmad Y. Abuhelwa ◽  
Stuart Mudge ◽  
David Hayes ◽  
Richard N. Upton ◽  
David J. R. Foster
Keyword(s):  
Transit Time ◽  
Gastrointestinal Transit ◽  
Correlation Model ◽  
Gastrointestinal Transit Time ◽  
Model Drug

In vivo hepatic clearance of lipophilic drugs predicted by in vitro uptake data into cryopreserved hepatocytes suspended in sera of rats, guinea pigs, monkeys and humans

Xenobiotica ◽  
2018 ◽  
Vol 49 (8) ◽  
pp. 887-894 ◽  
Author(s):  
Takashi Koyanagi ◽  
Koji Yano ◽  
Soonih Kim ◽  
Norie Murayama ◽  
Hiroshi Yamazaki ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Hepatic Clearance ◽  
Lipophilic Drugs ◽  
Uptake Data ◽  
In Vitro Uptake
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